After losing its luster because of concerns over potentially serious adverse effects, this drug is drawing increasing respect. Results from the Bipolar Affective disorder Lithium/ANti-Convulsant Evaluation (BALANCE) study show that combining valproate with lithium is more likely to prevent relapse in patients with bipolar disorder than valproate alone, with 41% relative benefit for the combination therapy. The benefit was independent of baseline illness severity, lasted for up to 2 years, and was most apparent in prevention of manic relapse. This study, along with other recent research, goes a long way toward putting lithium back on top as the preferred treatment for bipolar disorder, said lead study author John R. Geddes, MD, professor of epidemiological psychiatry and director of the Oxford Clinical Trials Unit for Mental Illness, Department of Psychiatry, University of Oxford, United Kingdom. “We’ve got more evidence purporting the lithium efficacy, safety, and its antisuicidal effects than we’ve ever had before,” Dr. Geddes told Medscape Psychiatry. “So don’t throw lithium away; it’s a highly effective treatment, and if people can tolerate it, then it’s worth trying.” The study was published online December 23, 2009, in The Lancet.
Challenging Guidelines

Although the study could not confirm a benefit of the valproate-lithium combination therapy over lithium alone, its findings should challenge current clinical guidelines that recommend valproate monotherapy as a first-line option for long-term treatment of bipolar disorder. The randomized, open-label trial included 330 men and women 16 years and older with bipolar 1 disorder for whom long-term drug therapy was indicated.
After a 4- to 8-week run-in during which patients received both lithium carbonate and valproate semisodium, subjects were randomly allocated to 1 of 3 groups:
• Continuation of combination lithium plus valproate;
• Switch to lithium monotherapy; or
• Switch to valproate monotherapy.
Study subjects remained on the allocated treatment for 2 years or until treatment failure. Lithium Standard Treatment Lithium, a soft, light metal element, was introduced on the market about 50 years ago. It was the standard maintenance treatment for bipolar disorder for more than 4 decades. However, the drug can be toxic and not all patients can tolerate it.

During the study’s follow-up period, the primary outcome — time to new intervention for an emerging mood episode, including drug treatment or hospital admission — occurred in 59 of 110 patients (54%) receiving combination therapy, 65 of 110 (59%) taking lithium, and 76 of 110 (69%) taking valproate. The hazard ratios for the primary outcome were 0.59 for combination therapy vs valproate, 0.82 for combination therapy vs lithium, and 0.71 for lithium vs valproate. Taking into account baseline severity of disorder, as measured by the number of previous admissions, and the nature of the most recent mood episode did not alter the outcome. The difference between treatments was constant up to 2 years, and exclusion of events occurring in the first 3 months did not significantly change the results.

Hospital Admissions

The risk for hospital admission for participants allocated to combination therapy was significantly lower than forthose allocated to valproate (adjusted hazard ratio of 0.51 for valproate patients compared with combination therapy patients). The benefit of the combination therapy compared with valproate was most apparent for manic relapses, whereas the advantage of lithium compared with valproate was most apparent for depressive relapses. “In terms of prevention of relapse, it’s clear that lithium is better than valproate from this study,” said Dr. Geddes. He added that the results suggest that nonresponders to long-term lithium treatment should continue taking lithium combined with valproate. The effect of adding lithium to valproate was “striking,” and this effect could be even larger in highly adherent patients with optimum therapy, said the study authors. According to Dr. Geddes, the effect was “additive” rather than synergistic.

The 3 groups did not differ in self-harm, quality of life, or global functioning. Most patients who responded — 95% taking lithium, 92% taking valproate, and 100% receiving combination therapy — reported at least 1 nonserious adverse event during follow-up. There were 7 serious adverse events among patients receiving valproate (3 deaths), 5 among those taking lithium (2 deaths), and 4 among those receiving combination therapy (1 death).
Careful Monitoring
Because lithium can have serious adverse effects, patients taking this drug have to be monitored carefully. “Toxicity and overdose [are] very high; so it’s a tricky drug to use,” said Dr. Geddes. However, he said, there is no good evidence of irreversible effects on the kidney, and so it’s not absolutely contraindicated in patients with renal failure. “It just means you have to be cautious.” Dr. Geddes pointed out that lithium is the only drug that reduces suicide in this patient population. Over the years, there has been a major shift away from prescription of lithium, especially in North America. In the United States, lithium prescriptions for outpatients nearly halved between 1992 and 1996 and 1996 and 1999, whereas the rate of prescription of valproate almost tripled, according to background information in the paper. By the start of this trial, valproate “was rapidly taking over” from lithium, with patients only receiving combination therapy after failure of the monotherapy, said Dr. Geddes. A patient with a first or second episode of mania would likely be treated with valproate and continue taking that drug. Indeed, clinical guidelines suggest valproate monotherapy as a first-line long-term therapy. Within that context, the study results are “very important,” said Dr. Geddes. “It suggests that people will do a lot better if they’re treated with lithium plus valproate rather than just be continued on valproate.” Compared with some studies, this randomized trial was more reflective of “the real world” because most patients were recruited from nonteaching centers, said Dr. Geddes. These included 41 sites in the United Kingdom, United States, France, and Italy. A limitation of the study was that treatment allocation was not masked from the investigators or participants. However, patients who had a strong preference for an investigational therapy were excluded from the study. Bipolar disorder is a disabling mental illness that is characterized by episodes of both elevated or irritable mood and depression. It is one of the most important causes of disability for patients between the ages of 15 and 44 years.
Outstanding Work
In an accompanying editorial, Rasmus W. Licht, MD, Mood Disorders Research Unit, Aarhus University Hospital, Risskov, Denmark, praised the BALANCE study, describing it as “outstanding work” and “an impressive example of international collaboration.” He said that even without a placebo group, the study “confirms the long-term efficacy of lithium, not only for the prevention of mania but also for prevention of depression.” On the basis of the study’s results, “the BALANCE group rightly challenges the recommendation by present clinical guidelines that valproate monotherapy is a first-line option for long-term treatment.”
Dr. Geddes has received research funding from the Medical Research Council, Economic and Social Research Council, National Institute for Health Research, and the Stanley Medical Research Institute and has received donations of drugs supplies for trials from Sanofi-Aventis and GlaxoSmithKline. He has acted as an expert witness for Dr Reddys but otherwise has received no payment from drug companies in the past 3 years. For conflict of information on other authors, see the original article. Dr. Licht has served on advisory boards for Bristol-Myers Squibb and AstraZeneca and has received unrestricted grants from GlaxoSmithKline Denmark, honoraria for lectures from Eli Lilly, Jansen-Cilag, GlaxoSmithKline, Bristol-Myers Squibb. and Pfizer, and travel and accommodation fees from Bristol-Myers Squibb.
The Lancet. Published online December 23, 2009.

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